Microbe Engineering of Drimane-type Building Blocks for Chiral Pool Synthesis of Meroterpenoids

Drimane-type merosesquiterpenoids (DMTs) are a class of natural products with diverse structures and broad biological activities. Classical DMT synthesis relies on atom-inefficient plant-derived chiral pool building blocks, while alternative drimane-type building blocks like drimenol and albicanol offer more direct routes but face production challenges. Herein, we engineered a microbial platform for efficient production of these building blocks. By optimizing the PhoN-IPK system through rational engineering and incorporating a Nudix hydrolase, we achieved a drimenol production of 398.4 mg/L and high albicanol titers of 1804.9 mg/L in shake flasks and 3.5 g/L in bioreactor. Structural analysis and molecular dynamics simulations of the engineered PhoN provided insights into its improved catalytic efficiency. We demonstrated the utility of this platform by synthesizing several DMTs using albicanol as the starting material, reducing synthetic steps and improving overall efficiency compared to classical approaches. This work presents a sustainable and cost-effective platform for producing valuable drimane-type building blocks, enabling efficient synthesis of complex DMTs with potential therapeutic and agricultural applications.